We propose to address a series of dietary and hormonal hypotheses related to cancers of the colorectum in the Nurses' Health Study Cohort. We expect 1490 incident cases of colorectal cancer among women with prospectively collected dietary data. The repeated measures of diet and other exposures will allow an assessment of long-term patterns as well as the impact of changes in diet and other exposures. We propose to build upon, extend, and refine observations we have already made on the dietary and hormonal influences of colorectal cancer. We propose to focus on 5 areas: (12) nutritional influences on DNA synthesis, of colorectal cancer. We propose to focus on 5areas: (1) nutritional influences on DNA synthesis, methylation, and repair; (2) tumor promoting hormonal and growth factors; and (5) non-steroidal anti- inflammatory drugs (NSAIDs) that inhibit cyclo-oxygenase-2 (COX-2). We propose to develop each of these areas through questionnaires over a 24-year period to better assess the impact of long-term exposures, to account for various induction periods, and to examine for the impact of change. We will also examine how hormones may underlie the basis of action for physical activity, body mass index, and weight change, and we will extract DNA from blood and buccal samples to examine hypothesized gene-environment interactions. In addition, we propose to acquire and utilize paraffin-embedded tissue specimens to examine how etiologic factors correlate with specific well-established molecular alterations (including the prevalence and spectrum K-ras mutations, level of microsatellite instability, prevalence of p16 hypermethylation, and the levels of p53, p21, p26, and COX-2 expression) in colon cancer. These studies are aimed to enhance our understanding of colorectal carcinogenesis and to provide a firm scientific foundation for future preventive efforts.